The purpose of this paper is to establish the pharmacokinetics and safety of escalating, once-daily doses of daptomycin, a novel lipopeptide antibiotic active against gram-positive pathogens, including those resistant to methicillin and vancomycin. This phase 1, multiple-dose, double-blind study involved 24 healthy subjects in three dose cohorts (4, 6, and 8 mg/kg of body weight) who were randomized to receive daptomycin or the control at a 3:1 ratio and administered the study medication by a 30-min intravenous infusion every 24 h for 7 to 14 days. Daptomycin pharmacokinetics was assessed by blood and urine sampling. Safety and tolerability were evaluated by monitoring adverse events (AEs) and laboratory parameters. Daptomycin pharmacokinetics was linear through 6 mg/kg, with a slight (ϳ20%) nonlinearity in the area under the curve and trough concentration at the highest dose studied (8 mg/kg). The pharmacokinetic parameters measured on the median day of the study period, (day 7) were half-life (ϳ9 h), volume of distribution (ϳ0.1 liters/kg), systemic clearance (ϳ8.2 ml/h/kg), and percentage of the drug excreted intact in urine from 0 to 24 h (ϳ54%). Daptomycin protein binding (mean amount bound, 91.7%) was independent of the drug concentration. No gender effect was observed. All subjects who received daptomycin completed the study. The frequencies and distributions of treatment-emergent AEs were similar for the subjects who received daptomycin and the control subjects. There were no serious AEs and no pattern of dose-related events. The pharmacokinetics of once-daily administration of daptomycin was linear through 6 mg/kg. For all three doses, plasma daptomycin concentrations were consistent and predictable throughout the dosing interval. Daptomycin was well tolerated when it was administered once daily at a dose as high as 8 mg/kg for 14 days.Daptomycin is a novel lipopeptide antibiotic that possesses several pharmacologic advantages over other gram-positive antimicrobial agents (3,12). It is a fermentation product of Streptomyces roseosporus that was discovered in the early 1980s (12). Daptomycin exhibits potent in vitro bactericidal activity against most clinically relevant strains of gram-positive bacteria, including antimicrobial-resistant pathogens (5). The MICs at which 90% of the microbes tested are inhibited are Յ1 g/ml, with the exception of those for enterococci, which are approximately 2 to 4 g/ml (5, 7, 8, 10-13). The spontaneous acquisition of resistance to daptomycin is rare in gram-positive bacteria in vitro, and the emergence of resistance to daptomycin is rare during clinical trials.Daptomycin appears to bind to the gram-positive bacterial cell membrane by its fatty acid tail, followed by calcium-dependent insertion (6). The resulting decrease in membrane potential causes cell death by rapidly stopping DNA, RNA, and protein synthesis (1). Because daptomycin does not appear to penetrate into cells, the interactions with the plasma membrane are most likely the basis for its pharmacologic actions...

No abstract

SUMMARY Ocular and cardiovascular effects of carteolol 2%, timolol 0O5%, and dummy eyedrops have been measured in a single dose double-blind crossover study in six healthy volunteers. Both drugs lowered intraocular pressure and reduced exercise-induced tachycardia. Neither produced a significant change in resting heart rate or blood pressure. The two agents appear comparable as regards ocular hypotensive and cardiovascular effects.Topical beta adrenoceptor blocking drugs (beta blockers) are now the first line of treatment in many types of glaucoma, though their use in certain individuals is restricted by adverse cardiovascular or respiratory effects resulting from systemic absorption. Timolol has been reported to cause bradycardia, syncope, arrythmias, and exacerbation of obstructive airways disease.' In theory beta blockers with differing properties such as cardioselectivity, partial agonist activity (intrinsic sympathomimetic activity; ISA) or reduced lipid solubility should offer advantages over timolol with respect to these adverse effects. This paper reports a comparative study of intraocular pressure (IOP) and cardiovascular effects of timolol and the newly introduced topical beta blocker, carteolol. Material and methods SUBJECTSSix healthy subjects, three female and three male, aged 33 to 57 years, took part in this study. None had a previous history of cardiovascular or respiratory disease or was taking drugs of any kind. All had normal eyes, IOPs, blood pressure, peak expiratory flow, electrocardiogram, blood count, and electrolytes. The subjects were phenotyped for debrisoquine hydroxylation,2 and all were extensive metabolisers (range of metabolic ratios 0-2 to 1-7). Non-metabolisers of debrisoquine were excluded because they may be prone to prolonged effects from small systemic doses of certain beta blockers.Each gave written consent to participate and the study was approved by the Ethical Committee of West Lambeth Health Authority. TREATMENTS AND STUDY DESIGNSubjects attended on three occasions at the same time of day separated by at least seven days. On each occasion one of three treatments, carteolol 2%, timolol 0.5%, or a matching dummy solution, was administered double blind as eyedrops in a complete balanced crossover design. Two drops of drug solution (volume 0-027 ml each) were applied one minute apart to one eye, the same eye being used in each volunteer for all treatments. MEASUREMENTSBefore and 2 and 4 hours after treatments the following measurements were made in the order given. The IOP was measured by applanation tonometry under proxymetacaine 0.5% local anaesthesia. Three readings were recorded from each eye on each occasion, the tonometer dial being read by an independent observer. Following a 10-minute supine rest period, the heart rate (HR) was recorded from an electrocardiography (ECG) and blood pressure (BP) measured by sphygmomanometry. The BP was recorded as mean BP (diastolic plus one-third pulse pressure). The HR was then measured during the last 15 seconds of an exercise peri...

Background and ObjectivesThe combination of cromolyn and ibuprofen is being investigated as a treatment for early Alzheimer’s disease (AD). This study investigated the pharmacokinetics, safety, and tolerability of cromolyn and ibuprofen co-administration in healthy elderly adult volunteers.MethodsIn this open-labeled study, 26 subjects, aged 55–75 years, received co-administration of inhaled cromolyn (single dose 17.1 mg; double dose 34.2 mg total) and oral ibuprofen (single dose 10 mg; double dose 20 mg total). Blood sampling was performed for 6 h after co-administration in all subjects; cerebrospinal fluid (CSF) was collected in three to four subjects per cohort for 4 h following co-administration. Safety parameters, including adverse events (AEs), were monitored throughout the study.ResultsFor cromolyn, the mean (±SD) maximum observed concentration (C max) in plasma was 46.69 ± 32.97 and 96.75 ± 46.22 ng/ml after single- and double-dose inhalation, respectively [time to C max (t max) ~22 min for each; terminal elimination half-life (t ½) ~1.8 h for each]. For ibuprofen, the plasma C max was 1090.98 ± 474.64 ng/ml and 2062.96 ± 655.13 ng/ml after single- and double-dose oral administration, respectively (t max ~1.6–1.8 h; t ½ ~1.9 h for each). For cromolyn, the CSF C max was 0.24 ± 0.08 ng/ml at 3.72 ± 0.70 h after single-dose administration and 0.34 ± 0.17 ng/ml at 3.45 ± 0.95 h after double-dose administration, and for ibuprofen, the CSF C max was 3.94 ± 1.29 ng/ml at 2.55 ± 0.96 h after single-dose administration and 8.93 ± 3.29 ng/ml at 3.15 ± 1.05 h after double-dose administration. Three (12%) subjects reported mild or moderate AEs which were unlikely to be related to study drug.ConclusionsThe combination of cromolyn and ibuprofen was safe and well tolerated. The concentrations of cromolyn and ibuprofen observed in the CSF are considered sufficient to titrate the estimated daily amyloid production and the associated inflammatory response in patients with AD.Electronic supplementary materialThe online version of this article (doi:10.1007/s40261-017-0549-5) contains supplementary material, which is available to authorized users.